Diego Pizzagalli, Ph.D. and Randy Auerbach, Ph.D.

Harvard Medical School

Funded in December, 2013: $300000 for 3 years

Identifying potential biomarkers for depression in teenagers

Investigators will use psychological testing and imaging in teenage girls whose mothers have major depressive disorder to determine whether specific neurological factors predict which of the adolescents will similarly develop depression.

Major depressive disorder (MDD) is estimated to affect as many as one in every 12 adolescents. Moreover, about one in five teenagers will have experienced a depressive episode by the time they reach their 18th birthday. Teenage girls are disproportionately affected. By age 15, girls report twice as many depressive episodes as boys, and this difference persists throughout adulthood. One of the strongest risk factors is having a parent with MDD. Children with a depressed parent are two to three times more likely than other children to develop MDD. Moreover, the risk is especially pronounced when the depressed parent is the mother: 40 percent of these children develop depression or other mental illnesses, particularly anxiety and substance addiction. Yet in spite of these profound associations, scientists do not know what factors in the brain make these teenagers prone to developing depression.

Based on prior research by these and other clinical scientists, the McLean investigators have several hypotheses about the neural bases of the link between maternal MDD and the subsequent high risk of their children developing this illness in mid-adolescence. Their hypotheses focus on the interaction of two brain chemicals, one of which may activate stress responses while the other may blunt the brain’s reward pathways. This combination may lead to a lessening of a person’s pleasure derived from good events while heightening responses to stressful situations. Specifically, the McLean researchers hypothesize that risk is conferred to an adolescent when: 1) their mother secretes higher than normal amounts of a factor (called corticotropin-releasing factor- CRF) during pregnancy, which is associated with abnormal reactivity to stress; and 2) exposure to high CRF levels during gestation produces in the offspring long-lasting changes in glutamate neurotransmission that blunt the child’s and adolescent’s reward pathways in the brain.

They will test these hypotheses in clinical studies using psychological tests and imaging in 40 teenage girls aged 12-14 whose mothers have MDD and who are therefore at increased risk of developing MDD themselves by age 15 or so. They will similarly study 40 girls of the same age whose mothers do not have MDD, and contrast the findings. Additionally, they will also test the mothers of both groups of girls. The investigators are restricting the study to girls because this provides for a more homogeneous population, with fewer variables that might affect the findings, and because girls report more depressive episodes than boys, so they are more likely than boys are to encounter depressive episodes during the course of the study. They will, however, seek funding from other sources to undertake similar research in boys.

Both groups—the healthy volunteer teenager girls and those at-risk for developing MDD--will complete a clinical interview and provide self-report information on day one. That day as well, the mothers of girls in both groups will participate in the standard interview used to assess current and past history of MDD and related disorders. On day two, the healthy volunteer adolescent group and those in the at-risk group will undergo neuroimaging. MRS (magnetic resolution spectroscopy) imaging will measure glutamate levels in target brain areas (called rACC and mPFC) to see if the at-risk participants, compared to the volunteers, have higher glutamate levels.

During fMRI, the healthy and at-risk adolescents will undertake tasks that involve rewards (peer approval and monetary gains) and tasks that are stressful (peer rejection and monetary loss). Investigators anticipate that the at-risk teenage girls, as a group, will have less reaction to the rewarding situations and heightened stress to the unfavorable situations compared to their healthy counterparts. Investigators expect imaging results to show that the at-risk girls, compared to the healthy volunteers, exhibit more neural dysfunction in CRF-related glutamate levels corresponding to blunting of reward pathways. Thereafter, all participants will be followed-up every three months over two years. The teenagers and their mothers will report on whether the teenagers have depressive symptoms and perceived stress. If the investigators’ hypotheses are correct, the at-risk group will have substantially more of both types of symptoms.

Significance: The study’s findings could potentially lead to the identification of key biomarkers indicating likely development of MDD in female adolescents, providing biological targets for prevention or early treatment.

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